Candidate: The candidate, Leigh Perreault, MD, is a board-certified internist and endocrinologist with experience in epidemiologic, basic science, and clinical research spanning the past decade. Her most recent work examining gender differences in insulin action following acute exercise was supported by an Award from the Endocrine Fellows Foundation. This project has yielded novel and important differences which have layed the foundation for continuing research in the area exercise fuel metabolism as it pertains to insulin action. Without reservation, the most outstanding career goal is for the candidate to achieve excellence as an independent physician-scientist. The Mentored Patient-Oriented Research Career Development Award would provide the necessary training to pursue and achieve this goal. Career Development: The training plan consists of two primary elements: 1) the acquistion of an impressive number of new research skills via the local mentors as well as three scheduled apprenticeships away; and 2) educational activities, including formal classroom work, as well as attendance and participation in national meetings, local seminars and journal clubs, and one-on-one mentor interactions. Research Plan: The overall aim of the proposed project is to delineate gender differences in the development of insulin resistance in skeletal muscle. Understanding such differences would help expand our knowledge of the pathophysiology of insulin resistance itself, as well as aid in the targeting of insulin sensitizing therapy. The general hypothesis is that men and women with impaired glucose tolerance (IGT) develop insulin resistance in skeletal muscle through different mechanisms. Specifically, we hypothesize that this occurs via decreased oxidative capacity in women, and decreased action of peroxisome proliferatoractivated receptor (PPAR) alpha (and its target genes) in men. Furthermore, exercise training in women, and fibrate therapy in men, will attenuate these derangements. State-of-the-art tecnhiques will be imployed. Environment: The environment for the candidate's training is exceptional. The mentor, Robert H. Eckel, MD, is an international expert in the area of insulin action and substrate uptake and, furthermore, is a proven mentor. The co-mentor, Christopher A. DeSouza, PhD, is a rising star in academic research with expertise in exercise and substrate use. Collectively, the mentors, collaborators, and institutional commitment excels.